Wild-type vesicular stomatitis virus (VSV) replicates to high titer in BHK-21 cells in vitro and in vivo in brains and spinal cords of intracerebrally (i.c.) infected mice. Both in vitro and in vivo, wild-type VSV infection is highly cytocidal. Certain temperature-sensitive (ts) mutants, principally ts 31 and ts 22, produce a slowly progressive central nervous system (cns) disease after i.c. inoculation. On the other hand, other ts mutants, i.e. ts 11 or ts 41, care avirulent. Accompanying the slowly progressive CNS disease induced by ts 31 and ts 22, are marked spongioform changes in spinal cords of affected mice. The spongioform myelopathy appears almost exclusively in grey matter and is centered primarily in neurons astrocytes and neuronal processes. Ts virus is recoverable from affected spinal cords coincident with demonstration of the histopathological lesions. In addition, i.c. infection with homologous defective-interfering (DI) particles and wild-type VSV also results in a slowly progressive and invariably fatal CNS disease. This proposal plans to study the pathogenesis of slowly progressive CNS disease induced by certain ts mutants of VSV as well as homologous DI particles and wild-type and/or ts mutants of VSV. Approaches will include: (a) A sequential study of infection in mice produced by wild-type VSV, or ts 31 or ts 22 VSV, or homologous DI particle-wild-type VSV and/or ts mutant VSV; (b) Sequential virological, histopathological and immunofluorescent studies in CNS infection produced by these viruses; and (c) an analysis of the biochemical defects in ts RNA and viral protein synthesis as they may relate to altered CNS disease and histopathological lesions observed.